The present invention relates to a new process for preparing a series of cephalosporin derivatives by replacing a carbamoyloxymethyl group at the 3-position of a 7-acylaminocephalosporin derivative by a substituted thiomethyl group.
Numerous 7-acylaminocephalosporin compounds have been prepared and many are known to have bacterial activity. In particular, certain cephalosporins having a heterocyclic thiomethyl group (for example a thiazolylthiomethyl group or a tetrazolylthiomethyl group) have been found to possess particularly effective antibacterial activity.
Accordingly, many processes have been proposed for replacing substituents at the 3-position of various cephalosporin compounds by heterocyclic thiomethyl groups. Among the techniques which have been proposed are the following:
1. Reacting a cephalosporin compound having an acetoxymethyl group at its 3-position with a heterocyclic thiol, as disclosed in "Cephalosporins and Penicillins--Chemistry and Biology", edited by Edwin H. Flynn, pages 158-159, Japanese Patent Publications Nos. 39-17936 and 49-45880, and Japanese Patent Application (laid open) No. 50-154287.
2. Reacting a cephalosporin compound having a carbamoyloxymethyl group at its 3-position with a heterocyclic thiol, as disclosed in Japanese Patent Application (laid open) No. 50-83383.
In the two methods described above, the reactions are carried out in water or in an aqueous organic solvent at a pH of 6-7, the amount of water used in these proposals generally being from 10 to 30 times the weight of the starting material.
More recently, cephalosporin compounds having a methoxy group at the 7.alpha.-position have been developed and certain of these have been reported to have potent antibacterial activity against a wide range of bacteria. Many of these compounds have a substituted thiomethyl group at the 3-position of the cephem nucleus and most are initially prepared from cephamycin C. As cephamycin C has a carbamoyloxymethyl group at its 3-position, this group has to be replaced by a substituted thiomethyl group. Known methods of effecting this replacement, such as those described above, give low yields and are commercially unattractive.
There has recently been published in Japanese Patent Application (laid-open) No. 53-98987 a proposal to replace the carbamoyloxymethyl group at the 3-position of cephalosporin compounds by a substituted thiomethyl group by reacting the cephalosporin compound with a suitable thiol in the presence of boron trifluoride or a complex thereof in an organic solvent without using water or an aqueous organic solvent. However, 7.alpha.-methoxycephalosporin compounds are decomposed by boron trifluoride and this method cannot, therefore, be used with such compounds.
There is, therefore, a need for a process which is capable of replacing a carbamoyloxymethyl group at the 3-position of a cephalosporin compound (whether or not it has a 7-methoxy group) without decomposing the compound and giving the desired product in high yield.